Why Do Some People Drink Too Much?

A sizable minority of the population abuses alcohol. Research has found that some vulnerability to developing alcohol-related problems is conveyed genetically, and animal research has indicated that inheritance can take many forms. Studies in mice have demonstrated that various individual genes or groups of genes can shape very distinct responses to alcohol. By identifying the proteins these genes encode and the mechanisms by which the genes influence an animal’s biochemical response to alcohol, scientists can gain insight into the features of human alcoholism and provide a basis for developing pharmaceuticals that short-circuit these genetically defined processes.

A lcohol is available to any adult, and illegally to many minors, in the United States. Although most people abstain or drink safely, a sizable minority of the population abuses alcohol. Understanding why alcohol leads to trouble for many, but not most, people exposed to it is the goal of re s e a rc h on the cause (i.e., etiology) of alcohol abuse and alcoholism. It is already clear that some vulnerability to deve l o p i n g a l c o h o l -related problems is conve ye d g e n e t i c a l l y, and animal re s e a rch has indicated that inheritance can take many forms. Studies in mice have demonstrated that various individual genes or g roups of genes can shape ve ry distinct responses to alcohol, such as a pre f e re n c e for alcohol over water, sensitivity to a l c o h o l's intoxicating effects, and the tendency to develop tolerance to it. By identifying the proteins these genes encode and the mechanisms by which the genes influence an animal's biochemical response to alcohol, scientists can gain insight into the features of human alcoholism and provide a basis for d e veloping pharmaceuticals that shortc i rcuit these genetically defined pro c e s s e s .
Another goal of re s e a rch on the genetics of alcoholism in humans is to determine to what extent individual d i f f e rences in alcohol-related behavior a re due to genetic versus enviro n m e n t a l influences. For example, in twin studies as much as two-thirds of the va r i a b i l i t y in drinking behavior in one population could be attributed to genetic factors in both men and women. Other twin studi e s a re investigating the re l a t i ve magnitude of various influences on alcohol consumption in youth. Identifying the genes that convey risk of alcoholism is a second major goal of genetic re s e a rc h ; scans of the human genome re veal evidence of genes in certain chro m o s o m a l regions that influence alcoholism.
Understanding how inborn vulnerability plays out in the temperament and behavior of an individual and in the context of family, peers, and culture is the goal of psychosocial re s e a rch on the cause of alcoholism. The traits and family characteristics of children at risk because of a family history of alcoholism also predict risk in children of nonalcoholic parents. If alcoholism re p re s e n t s the end result of a sequence to which many factors contributed, then the hope is that by understanding the contributors and how they interact, it also will be possible to intervene before vulnerability becomes a destru c t i ve illness.

Animal Genetic Studies on Alcoholism
Vulnerability to alcohol dependence and abuse is partly determined by genes. Howe ve r, no single gene is re s p o n s i b l e for alcohol abuse and dependence; r a t h e r, many genes that play roles in a variety of normal human behaviors and sensory perception are invo l ve d . Identifying all the genes invo l ved is a p roject of enormous magnitude and d i f f i c u l t y, because of the size of the Why Do Some People Dr i n k Too Mu c h ? [alcohol or other drug] use, abuse, and dependence); genetic trait; QTL mapping; genetic linkage; twin study; family AODU history; AOD sensitivity; protective factors; psychological development; attitude toward AOD human genome 1 and the complexity of the behaviors invo l ved in abusive drinking and dependence. The Human Ge n o m e Project (HGP) (supported in the Un i t e d States by the National Institutes of Health and the U.S. De p a rtment of Energy) has been an important impetus to the search for genes invo l ved in alcoh o l -related behaviors. HGP re s e a rc h e r s a re working tow a rd the goal of identifying e ve ry gene and the protein it encodes and mapping each gene to a precise locat i o n (i.e., locus) on one of the chro m os o m e s . 2 This re s e a rch is providing the tools with which scientists can inve s t i g a t e the genetic underpinnings of a range of human disorders and conditions, including alcohol abuse and dependence. Even with these advances in understanding the human genome, howe ve r, re s e a rchers continue to rely on animal models to investigate the causes and consequences of alcoholism.

A sizable minority of the population abuses alcohol. Research has found that some vulnerability to developing alcohol-related problems is conveyed genetically, and animal research has indicated that inheritance can take many forms. Studies in mice have demonstrated that various individual genes or groups of genes can shape very distinct responses to alcohol. By identifying the proteins these genes encode and the mechanisms by which the genes influence an animal's biochemical response to alcohol, scientists can gain insight into the features of human alcoholism and provide a basis for developing pharmaceuticals that short-circuit these genetically defined processes. KE Y W O R D S: genetic theory of AODU (AOD
As mentioned pre v i o u s l y, vulnerability to alcohol dependence in humans and alcohol pre f e rence in animals are complex behaviors that are determined by multiple genes. Such traits are know n as multigenic or quantitative traits. Rather than being simply present or absent, such traits are expressed along a spectru m f rom high to low. A technique deve loped in recent years for conducting the s e a rch for genes influencing such traits (i.e., quantitative trait loci [QTLs]) is called QTL mapping. This approach is based on the concept of linkage, which posits that genes located close together on the chromosome are more likely to be inherited together from one pare n t than are two genes farther apart. This technique provides a means of locating and measuring the effects of a single QTL on an observable trait or behavior (i.e., phenotype).

Creating Rodent Models
Studies of animal genetics are useful because of fundamental limitations in human genetic studies. For example, the genetic blueprint of each human s u b j e c t -e xcept for those of identical twins-is unique, as are each person's b a c k g round and experiences. In contrast, laboratory re s e a rchers can contro l the mating of mice and rats over many generations and there by produce strains of animals in which all individuals are genetically identical. Fu rt h e r m o re , re s e a rchers can control the enviro n m e n t s of the animals. Because of the high degre e of genetic similarity among individual animals and the extent of enviro n m e n t a l c o n t rol, re s e a rchers can attribute the d i f f e rences in an alcohol-related behavior b e t ween two genetically dissimilar animal strains to differences in their genetic m a k e u p. Mo re ove r, because humans and rodents share most of their genes and because these genes produce pro t e i n s i n vo l ved in identical physical pro c e s s e s in both species, the results of such animal genetic studies can provide insights into human genetics.
Animal genetics re s e a rchers use a variety of approaches to selectively bre e d mice and rats that display alcohol-re l a t e d phenotypes similar to those of humans. Comparing the genetic makeup of different mouse strains should allow re s e a rc h e r s to identify genetic underpinnings of the re s p e c t i ve alcohol-related phenotypes.
Many re s e a rchers use mice fro m re c o m b i n a n t -i n b red (RI) strains, espe-cially mice from the BXD series, which contains 25 different strains. The series was created by crossing two mouse strains that are genetically distinct and differ from each other phenotypically in many ways, including many alcoholrelated traits. Next, the re s e a rc h e r s i n b red many different pairs of offspring ( b rother-sister mating), which re s u l t e d in different strains of mice. Each mouse within a strain is genetically identical to e ve ry other mouse in that strain, but b e t ween any two of these strains only 50 percent of their genes are share dthe same amount that human siblings s h a re. Thus, the different alcoholrelated traits observed in the pare n t s we re sorted into individual animals and then fixed genetically. For example, RI mice from different strains can differ in their pre f e rences for alcohol. The task for re s e a rchers then becomes to look for differences in the genetic makeup of these RI strains that might account for some of the differences in their alcohol pre f e rences and to narrow the possible location of the re s p o n s i b l e genes to specific chromosomal re g i o n s .

QTL Mapping
QTL mapping relies heavily on statistical analyses. These analyses are used to m e a s u re the degree of association betwe e n a marker and the phenotype under i n vestigation to determine the magnitude of the effect of the QTL on the phenotype and to assess the statistical significance of the observed association b e t ween the marker(s) and the QTL. If the QTL is located close to the mark e r and has a large effect, then d e t e c t i o n and mapping can be perf o r m e d e a s i l y and accurately using simple stat i s t i c a l methods (e.g., re g ression analysis). If the QTL is farther away from the mark e r gene, a more complex and statistically optimal method called interval m a pping can be used. Re c e n t l y, re s e a rc h e r s h a ve developed still more sophisticated statistical methods, resulting in more accurate QTL mapping.

Recent Studies of Alcohol-Related QTLs
In recent years, re s e a rchers have used the techniques described above to identify provisional QTLs for genes invo l ve d in several alcohol-related phenotypes exhibited by mice, including alcohol p re f e rence (which may reflect the rew a rdi n g p ro p e rties that are closely related to a l c o h o l's addictive potential), sensitivity to alcohol's sedative-hypnotic effects, and withdrawal. Howe ve r, although many of these provisional QTLs will be subsequently confirmed by more refined studies, an unknown number will likely be found on further examination to be false positives. In addition, re s e a rchers are concerned about the potential for false negatives, or missing QTLs that are really there. There f o re , subsequent confirmation of prov i s i o n a l QTLs using other approaches is a statistical necessity.
One study screened the entire genome for major QTLs that might be invo l ve d in alcohol pre f e rence, identifying two loci, Alcp1 and Alcp2 (Melo et al. 1996). The two QTLs are gender specific, with Alcp1 being specific to males and Alcp2 being specific to females. Another series of studies focusing on sensitivity to alcoh o l's sedative-hypnotic effects identified 12 provisional QTLs, out of which 2 or 3 we re confirmed to be real. Fi n a l l y, thre e QTLs for withdrawal have recently been confirmed (Buck et al. 1997). Howe ve r, QTLs re p resent small chro m o s o m a l regions that can still contain numero u s genes. No one has identified an individual gene responsible for differential alcohol sensitivity in rodent models.

Shared Gene Actions
In other QTL mapping applications, i n vestigators are interested in whether two distinct phenomena, such as sensitivity to alcohol's effects and alcohol tolerance, result from the same underlying group of genes or from entire l y separate QTLs. Because of the large number of diverse alcohol-related behavi o r s c u r rently being investigated, analysis of potential shared gene actions is an i m p o rtant area for further work .
One study concluded that sensitivity and tolerance to alcohol are not mediated by common genetic factors (Ph i l l i p s et al. 1996). In contrast, other re s e a rc h e r s h a ve presented evidence suggesting comm o n a l i t y in function between genes f o r s e d a t i ve-hypnotic sensitivity to alcohol and genes specifying the distribution and l e vels of the brain chemical neuro t e n s i n , which plays a role in addiction (Erw i n et al. 1997). Another study eva l u a t i n g the relationship between sensitivity and tolerance found that most measure s examined we re not correlated, indicating that the traits had different genetic determinants (Crabbe et al. 1996). In general, there appear to be many more cases of different genes determining d i f f e rent measures of alcohol action, with re l a t i vely little commonality.

Recent Progress in the Genetics of Alcoholism
Twin, family, and adoption studies h a ve firmly established major roles for both genetics and environment in the etiology of alcoholism in humans. Su c h studies also have clearly demonstrated that alcoholism is a genetically complex d i s o rd e r, influenced by multiple genes that interact in an unknown fashion with each other and with similarly unknow n e n v i ronmental factors to produce the disease. It also seems likely that individuals in different families develop alcoholism under the influence of differe n t p redisposing genes.
Re s e a rchers have identified two genes influencing predisposition to alcoholism. These genes encode certain forms of the enzymes alcohol dehyd rogenase (ADH) and aldehyde dehyd rogenase (ALDH), both of which are invo l ved in alcohol metabolism. A defective variant (i.e., allele) of the ALDH2 gene, which is common in Asian populations, substantially (although not completely) protects carriers from developing alcoholism by causing a flushing reaction (e.g., facial flushing, nausea, vomiting, and a racing heart ) after drinking alcohol. Newer studies have suggested that certain ADH2 and ADH3 alleles also protect carriers to some extent f rom developing alcoholism. These prot e c t i ve alleles, which are also common in Asian populations, ultimately act thro u g h a mechanism similar to the defective ALDH2 allele, producing feelings of disc o m f o rt and illness and there by discouraging carriers of these alleles from consuming large amounts of alcohol.

Findings From Twin/Family Studies
Classic twin studies compare the re s e mblances for a trait of interest betwe e n monozygotic (MZ, identical) twins and dizygotic (DZ, fraternal) twins in ord e r to determine the extent of genetic influence, or heritability, of the trait. This comparison allows re s e a rchers to calculate heritability, because MZ twins are genetically identical, whereas DZ twins s h a re only half their genes. The appro a c h relies on the assumption, howe ve r, that for both MZ and DZ twins, enviro nments of both individuals in the pair are equally similar. Recent studies also have collected environmental data to allow c o r rections of the results for any deviation from this assumption. Fu rt h e r m o re , data on twins can be augmented by collecting data on their family members as well as the familial environment, there by p roviding information about how environmental factors interact with genetic p redisposition to produce a disease.
Prior to 1992, twin studies firmly established substantial heritability of alcoholism in men but not in women. Since then, howe ve r, several studies h a ve also re p o rted a substantial heri-tability of alcoholism in women. Fo r example, a study of adult Australian MZ and DZ twins suggested that about twot h i rds of the risk of becoming alcoholic was genetically mediated in both men and women, with the remainder of the risk determined by environmental factors not s h a red by the two members of a given twin pair (Heath et al. 1997). The data provided no evidence for a difference in the d e g ree of heritability in men and women, or for genetic factors operating in one gender but not the other. This last conclusion was particularly aided by analyses of data from opposite-sex twin pairs, a type of analysis not previously re p o rted.
Because people who eventually become alcoholic typically begin experimenting with alcohol use during adolescence, inve stigators have long been interested in factors influencing initiation of alcohol use during adolescence. A study among Dutch families, each consisting of a pair of adolescent twins and their parents, indicated that child re n's drinking behavior is influenced primarily by genetic and environmental factors other than their pare n t s' alcohol use ( Koopmans and Boomsma 1996). This conclusion is consistent with findings fro m p revious studies demonstrating strong peer influences on adolescent alcohol use.
Many alcoholics suffer from medical complications of alcoholism, such as live r cirrhosis, pancreatitis, card i o m yo p a t h y, or p s ychosis due to brain damage. The incons i s t e n c y with which medical complications occur in alcoholism has led to the hypothe s i s that susceptibility to these complications is influenced by genetic factors independent of those influencing susceptibility to alcoholism itself. Re s e a rchers tested this hypothesis in male MZ and DZ twin pairs f rom the U.S. World War II Era Ve t e r a n Twin Re g i s t ry, assessing the co-occurre n c e of alcoholism, cirrhosis, and alcoholic psyc h o s i s ( Reed et al. 1996). From the MZ and DZ concordance rates for the thre e diseases, the investigators calculated heritabilities of 0.59 for alcoholism (in general agreement with results of other studies), 0.47 for liver cirrhosis, and 0.61 f o r alcoholic psychosis. For each trait, the re m a i n d e r of the variance in susceptibility was due to environmental factors not s h a re d by members of a twin pair. Us i n g an analytic method that allowed for simult a n e o u s analysis of all three diseases, the i n vestigators calculated that 85 percent of the overall genetic risk was shared for alcoholism, cirrhosis, and psyc h o s i s .
Although many observers have noted that alcoholics smoke ve ry heavily, the re a s o n s for this dual substance use have been poorly understood. Recent twin s t u d i e s a re shedding considerable light on the reasons for this phenomenon. In one such study, re s e a rchers analyzed tobacco and alcohol use versus nonuse in adolescent and young adult Dutch twin pairs ( Koopmans et al. 1997). At all ages tested (12 through 25 years), regular alcohol use was highly correlated with regular tobacco use. For 12-to 16-year-olds, shared environmental factors (peer pre s s u re was ve ry likely prominent among them) influenced both smoking and drinking. For 17-to 2 5 -year-old men, howe ve r, both alcohol and tobacco use we re highly genetically determined, with shared enviro n m e n t a l influences playing a significant but lesser role. For 17-to 25-year-old women, alcohol use was highly genetically determined, and tobacco use was influenced by both genetic and shared environmental factors. Both in young adult men and women, the same genetic factors influenced alcohol as well as tobacco use. These findings suggest that while initial exposure to alcohol and nicotine is environmentally influenced, persistence in using these substances is under strong shared genetic influence.
The physiologic mechanism of the s h a red genetic influence on alcohol and tobacco consumption is currently a matter of speculation. One hypothesis is that individuals with high reactivity to stre s s may use both substances for stress re l i e f. A l t e r n a t i ve l y, use of either substance may induce physiologic tolerance to the other, leading to a need to consume gre a t e r amounts of the latter substance in ord e r to experience a subjective effect. Consistent with the latter hypothesis, several twin studies have suggested that smoking may i n c rease the risk of alcoholism by re d u cing sensitivity to alcohol.

Findings From Genetic Linkage Studies
Although twin and family studies can p rovide information about the genetic a rc h i t e c t u re of alcoholism and the re l a-tionship between genetic influences on alcoholism and other traits, they do not permit the identification of the specific genes influencing predisposition to alcoholism. Cu r rent efforts to identify such genes rely on genetic linkage and association studies. Such studies have re c e i ved enormous impetus in re c e n t years from the mapping of large numbers of human genetic markers and genes under the HGP and from the d e velopment of more sophisticated statistical methods for analyzing gene mapping data.
Genetic linkage studies can be designed in either of two principal ways. In the first design, investigators track the inheritance of the disease, along with that of genetic markers spanning the entire genome, through multigenerational families affected by the disease. In the second design, investigators measure the degre e to which pairs of siblings (or other re l at i ves) affected by the disease share different marker alleles. On average, simply by chance, siblings are expected to share half of the alleles of most of their genes. Howe ve r, two siblings affected by the same disease will more frequently share alleles of markers close to genes affecting p redisposition to, or pro g ress of, the disease. Under either design, markers show n to be genetically linked to a disease define a chromosomal region likely to contain a gene influencing the disease. The adva ntage of this approach to gene discove ry is that a sufficiently compre h e n s i ve mark e r m a p, such as that recently assembled by the HGP, permits an unbiased search of the entire genome without requiring any prior physiologic hypothesis about which genes might influence the disease.
The results of the first two systematic s e a rches of the entire human genome (termed genome scans) for genes influencing predisposition to alcoholism have recently been published. The first study, by the Collaborative Study on Genetics of Alcoholism (COGA), a National In s t i t u t e on Alcohol Abuse and Alcoholisms u p p o rted consortium of inve s t i g a t o r s at six centers across the United St a t e s , re p o rted results from a primarily Caucasian-American sample of 987 individuals from 105 families (Reich et al. 1998). This study found suggestive evidence for genes influencing suscepti-bility to alcoholism on chromosomes 1 and 7 as well as weaker evidence for a gene on chromosome 2. It also re p o rt e d modest evidence for a gene reducing the risk for alcoholism on chromosome 4. An independent genome scan, based on 152 subjects from a So u t h we s t e r n American Indian tribe, re p o rted suggest i ve evidence for a gene influencing susceptibility to alcoholism on chro m o s o m e 11 as well as suggestive evidence for a prot e c t i ve gene on chromosome 4 in approximately the same region implicated by the COGA study (Long et al. 1998).
It is not surprising that the two studies implicated different chro m o s o m a l regions because (1) American In d i a n s and Caucasian Americans (of Eu ro p e a n descent) have different genetic histories, and (2) the physiologic mechanisms leading to alcoholism in American Indians may be different from those in Caucasians. In view of these differe n c e s b e t ween the two subject populations, it is of interest that both studies found some evidence for a pro t e c t i ve gene in the same region of chromosome 4 (which includes, for example, the ADH2 and ADH3 genes).

Findings From Genetic Association Studies
Genetic association tests measure whether a particular allele of a gene occurs more frequently in individuals affected by a disease than in unaffected individuals. A finding of genetic association can indicate that the gene under study influences the disease. Although such tests re q u i re prior knowledge of the gene under study (unlike genetic linkage tests), they are statistically much m o re powe rful than linkage tests for detecting genes exe rting only small effects on predisposition to a disease. They are also easier to perform than linkage tests, requiring ascert a i n m e n t only of disease cases (and sometimes their parents) and controls rather than the entire nuclear families or large, multigenerational families re q u i red for linkage studies. Howe ve r, since an a p p a rent association between an allele and a disease can arise for reasons other than the influence of that allele on the disease, association studies need to be c a refully designed.
A group of seven such we l l -d e s i g n e d studies focused on the association of the ADH2 and ADH3 genes with alcoholism. A meta-analysis of these studies, which we re done in va r i o u s ethnically matched Asian subject samples, attempted to measure to what extent genetic variation in these genes affects the risk of alcoholism (Reich et al. 1998). The analysis found consistent results across the seven studies, firmly establishing that certain alleles of these genes reduce the risk that their carriers will develop alcoholism.
Genes encoding various components of the nerve signal transmission system using the brain chemical (i.e., neurotransmitter) dopamine also have been tested for association with alcoholism. In contrast to early re p o rts and despite some conflicting results, many we l ldesigned studies found no evidence for the association of the dopamine re c e ptor D2 with alcoholism. Some studies of the genes encoding other molecules in the dopamine pathway, howe ve r, h a ve produced suggestive results indicating an association with alcoholism that is worthy of further pursuit. These genes include alleles of the tyro s i n e h yd roxylase gene, which encodes an enzyme centrally invo l ved in dopamine synthesis and functional variants of another dopamine receptor called D4.
These examples demonstrate that most genes tested so far for association with alcoholism have already been suspected of playing a role in pre d i s p o s i t i o n to alcoholism. The power of genetic studies to re veal the influence of pre v iously unsuspected genes on pre d i s p o s i t i o n to alcoholism, there by affording insights into previously unre c o g n i zed disease mechanisms, thus remains to be exploited, at least in genetic association studies.

Psychosocial Factors in Alcohol Use and Alcoholism
No single, simple explanation exists for why some people develop problems with alcohol. Re s e a rch has shown that multiple pathways involving psyc h o s o c i a l variables can lead to behaviors that i n vo l ve alcohol consumption, ranging f rom simple alcohol experimentation to s e ve re alcohol dependence. Fu rt h e r m o re , d i f f e rent subtypes of alcoholism exist that may have different causes, or etiologies. Fi n a l l y, multiple biological and p s ychosocial factors mutually influence each other in causing alcohol abuse, and it would be incorrect to view psyc h o s ocial causes as either independent fro m , or competing with, biological causes. R a t h e r, alcohol use and alcoholism are best viewed as end products of a combination of biopsychosocial influences.
This section re v i ews recent psyc h o s oc i a l re s e a rch that has focused on four a reas: family history of alcoholism, deve lo p m e n t a l issues, motivations, and alcoh o l -related cognitions (i.e., beliefs about alcohol).

Family History of Alcoholism
A family history of alcoholism is a we l lestablished risk factor for the deve l o pment of alcoholism, although the majority of children of alcoholics (COAs) do not d e velop alcohol use disorders. COAs differ f rom children without a family history of alcoholism in several ways. These factors include a higher pre valence of mental and behavioral disorders, more adverse family e n v i ronments, and physiologic re s p o n s e s t o alcohol that are known to be associated with risk, in part i c u l a r, a lack of sensitivity to alcohol's intoxicating effects or an increased sensitivity to its anxietyreducing effects. These characteristics a re not unique to COAs, and the same factors that mediate risk of deve l o p i n g

Alcohol use and alcoholism are best v i e wed as end pro d u c t s of a combination of b i o p s yc h o s o c i a l i n f l u e n c e s .
alcohol problems in children with a family h i s t o ry may also explain the risk faced by those without a family history. Models that seek to explain how these risk factors interact to lead to alcohol-related problems suggest that COAs are exposed to higher leve l s of these risk factors than are other childre n . One source of the variation in the outcomes of COAs is that familial alcoholism occurs in different forms. Re c e n t studies suggest that the type of alcoholic Pre d i c t a b l y, young adult offspring fro m the families with alcoholism have eleva t e d l e vels of alcohol problems compared with peers with no family history of alcoholism ( Finn et al. 1997). In addition, offspring of the families with alcoholism and antisocial personality themselves have the highest levels of antisociality and n e g a t i ve affect (e.g., anxiety, depre s s i o n , and neuroticism) compared with offspring of other alcoholic families.
Similar findings have emerged from a community sample of children pre s c h o o l t h rough age 8 (Zucker et al. 1996). In a comparison of children of families without alcoholism, families with alcoholism, and families with coexisting alcoholism and antisocial personality disord e r, childre n whose families showed both alcoholism and antisociality had the highest leve l s of risk factors for developing alcohol p roblems and we re also most likely to maintain this risk over time.

Mediational Models
Recent investigations have attempted to understand the mechanisms or pro c e s s e s that underlie the effects of pare n t a l alcoholism on children. An import a n t a p p roach invo l ves the deve l o p m e n t and testing of mediational models that p rovide an overall conception of how p a rticular risk factors play out in the l i ves of the affected individuals. Thre e b road groups of theoretical models provide platforms for exploring the transmission of alcoholism from parent to child: "deviance proneness," "n e g a t i ve a f f e c t i v i t y" (or emotionality), and "s e nsitivity to the effects of alcohol." The main characteristics of these models, which are not mutually exc l u s i ve, but are i n t e r related and interacting, are as follow s : The deviance proneness model f o c u s e s on deficits in children in behavioral s e l f -regulation and socialization and on the cascade of effects that result fro m and interact with these deficits. Ac c o rd i n g to this model, COAs have difficult temp e r a m e n t s and experience poor pare n ting, both of which place them at risk for emotional distress and failure in school. This, in turn, raises their risk for affiliation with a deviant peer gro u p likely to promote alcohol use and misuse.
The n e g a t i ve affectivity model f o c u s e s on the importance of stress and negat i ve affect in explaining the transmission of alcoholism from generation to generation. Ac c o rding to this model, C OAs are exposed to high levels of life s t ress and are temperamentally hyperre a c t i ve to stress. These children deve l o p high levels of emotional distress and drink to re l i e ve these feelings. Models based on sensitivity to alcoh o l's effects a re founded on the hypothesis that COAs have greater sensitivity to a l c o h o l's stress re s p o n s e -d a m p e n i n g effects and less sensitivity to alcohol's n e g a t i ve effects.
At least some experimental evidence exists for each of these models.

The Role of Executive Functioning
Early conduct problems, which accordi n g to the deviance proneness model e vo l ve into a broad set of underc o nt rolled behaviors (e.g., alcoholism), may be related to neuro p s ychological deficits in exe c u t i ve functioning. Exe c u t i ve functioning encompasses the capacity for sustained attention, concentration, abstract reasoning, goal setting, anticipation and planning, and the ability to monitor one's own behavior (e.g., to inhibit inappropriate behavior and shift to adaptive behavior).
Poor exe c u t i ve functioning may predict increases in alcohol consumption among young adults with a family hist o ry of alcoholism. Se veral mechanisms may underlie the association of poor e xe c u t i ve functioning with alcohol p roblems. For example, children with poor exe c u t i ve functioning are more difficult to parent, evoke more punishment, and thus may develop poore r bonds to parents and poorer socialization. Mo re ove r, children with poor exe cu t i ve functioning are likely to experience m o re failure in school, which incre a s e s the risk of making friends with deviant peers and, subsequently, of escalating alcohol use in adolescence. Fi n a l l y, people with deficits in exe c u t i ve function also may be unable to regulate their ow n mood, making them more sensitive to s t ress. These people would be part i c ularly vulnerable to the stress re s p o n s edampening pro p e rties of alcohol.

The Role of Parenting and the Family Environment
Re s e a rchers have examined pare n t i n g and family environment in an attempt to understand both the transmission of alcoholism from generation to generation and the causes of alcohol use and misuse in the wider population. In general, low

Alcohol Research & Health
The same factors that mediate risk of d e veloping alcohol p roblems in childre n with a family history may also explain the risk faced by those without a family h i s t o ry.
l e vels of parental emotional support and a lack of control and monitoring of child behavior are linked to other adolescent p roblem behaviors, such as smoking and early sexual activity. Some of the parenting deficits in alcoholic families are associated with the d e velopment of early conduct pro b l e m s and early onset of alcohol use, which itself is a risk factor for later pro b l e m s with alcohol use. Children of these families may not learn emotional and behavioral self-regulation and may lack social skills, which also increases the likelihood of rejection by mainstream peer gro u p s and association with AOD-using peers. Such poor parenting and poor socialization may create a high risk of alcohol p roblems, not only for COAs, but also for adolescents from nonalcoholic families. Howe ve r, poor parenting may be a p roduct as well as a cause of behavioral difficulties in children. Thus, childre n with conduct disorders may evoke poor p a renting responses.

Protective Factors
Most COAs do not develop alcohol dependence. Ac c o rding to the mediational models described earlier, this would be partially due to these childre n not experiencing mediators of risk such as difficult temperaments or poor parenting. Alternative l y, COAs subject to these risk mediators may have good outcomes because their risk is buffere d by exposure to a pro t e c t i ve factor. Some recent evidence supports the existence of pro t e c t i ve factors. One 3year study of adolescents in alcoholic families found that these children we re less likely to begin using AODs if they p e rc e i ved that they had control ove r their environment, had good cognitive coping skills, and re p o rted that their families we re highly organize d ( Hussong and Chassin 1997). Ot h e r i n vestigators have found that in alcoholic families that pre s e rve family rituals, such as keeping to established daily routines and celebrating holidays, the young adult offspring are less likely to re p o rt problem drinking (Ha w k i n s 1997). Fu rt h e r m o re, the Na t i o n a l Longitudinal Study on Ad o l e s c e n t Health identified two factors that pro-tected children from taking risks in four health areas, including AO D abuse (i.e., abuse of cigarettes, alcohol, and marijuana), emotional health, violence, and sexuality. These two pro t e ct i ve factors we re parent-family connectedness and school connectedness. 3 Fi n a l l y, re s e a rchers found that pare n t a l s u p p o rt had a pro t e c t i ve effect, part i c ularly with childre n's mental health, a p p a rently by enabling adolescents to cope better with life stresses, there by p re venting them from turning to heavy d r i n k i n g .

Developmental Issues
Alcohol use and alcoholism can also be studied within the context of psyc h o s ocial development throughout the life span. Early developmental antecedents to alcoholism can be seen even in the p reschool years in the form of deficits in s e l f -regulation, emotional re a c t i v i t y, and conduct problems. For example, in one s t u d y, observers rated the temperaments of 3-year-old children; 18 years later the same individuals underwent diagnostic i n t e rv i ews (Caspi et al. 1996). Boys whose temperaments we re rated as underc o nt rolled (i.e., impulsive, restless, and distractible) or inhibited (i.e., shy, fearf u l , and easily upset) at age 3 we re more likely than other children to be diagnosed at age 21 as alcohol dependent or as having a l c o h o l -related pro b l e m s .
De velopmental re s e a rchers also look at age-related peaks and declines in alcohol use. Drinking usually begins in adolescence, and early initiation of alcohol use is a risk factor for alcoholrelated problems in adulthood. In general, the factors that predict alcohol i n vo l vement among adolescents are similar to those that predict other forms of adolescent problem behavior, such as delinquency and risky sexual behavior. These predictors include high life stre s s , n o n a d a p t i ve coping styles, parental and peer AOD use, little p a rental support, a l ow level of academic competence, and poor behavioral contro l .
In older adolescents and yo u n g adults, developmental changes re l a t e d to their new freedoms and re s p o n s i b i l ities influence their drinking behavior. For example, when young adults take on the responsibilities of work and marriage, they typically reduce their drinking and are less likely to re p o rt symptoms of alcohol abuse and dependence. One interpretation is that these individuals drink less during this period because drinking is incompatible with the obligations of adult roles. These findings are consistent with past re s e a rc h indicating that a subtype of alcoholism may be developmentally limited; that is, some people may drink heavily and h a ve alcohol-related problems in yo u n g adulthood but not in later years. In d e e d , i n vestigators are finding more evidence to support the idea that different subtypes of alcoholism start at different ages, and h a ve d i f f e rent causes. Establishing such classification schemes for alcoholics is not an abstract pursuit because the tre a t m e n t needs of these groups likely differ.

Motivation To Drink
One area of psychosocial re s e a rch on alcohol use focuses specifically on what m o t i vates individuals to drink. Pe r h a p s the most commonly studied motivation invo l ves alcohol's ability to re d u c e a n x i e t y, thus making it a way to cope with stress. The strength of the re l a t i o nship between stress and alcohol consumption may va ry across the life span, h owe ve r, being weaker in adolescents and more pronounced in older adults.

Stress Reduction
Some people use alcohol to cope with s t ress. One model proposes that negat i ve emotions (e.g., anxiety or depre ssion), the expectation that alcohol will re l i e ve these feelings, and coping styles c h a r a c t e r i zed by avoiding rather than c o n f ronting life issues all may incre a s e a person's motivation to drink in ord e r to cope with stress. Consistent with this model, these characteristics show the strongest correlation between stre s s and drinking. The evidence that some people use alcohol to reduce stress, howe ve r, is complex and inconsistent for a number of reasons, not least of which is that there are multiple determinants of alcohol use. Fu rt h e r m o re, the effect of p ro t e c t i ve factors that reduce the impact of stress on drinking (e.g., social support systems) complicates the evidence for the re l a t i o n s h i p. Fi n a l l y, problems such as a time lag between the occurrence of a s t ressful event and resulting alcohol use also may result in inconsistent findings. Thus, one study using daily diaries found that women consumed less alcohol in h i g h -s t ress weeks (perhaps because alcohol impaired their ability to cope with s t ressors) but consumed more alcohol after the stressful event was over (Bre s l i n et al. 1995).

Mood Enhancement
Other motives and determinants of alcohol use can ove r s h a d ow stre s s -re d u c t i o n m o t i ves. One model suggests that people who are characterized by high levels of sensation seeking or who expect that alcohol use will enhance positive mood will be more strongly motivated to drink for this effect (Cooper et al. 1995). Alcohol use to reduce stress or enhance p o s i t i ve mood are not mutually exc l u s i ve m o t i vations to drink, howe ve r, and they can be observed in the same person. The most seve re alcohol problems have been re p o rted in people who are characterize d by both high levels of negative affect and l ow levels of constraint.

Alcohol's Effect on Emotional State
Questions remain as to how exactly alcohol affects emotional state. Laboratory data show that alcohol dampens re s p o n s e s to stress; at the same time, howe ve r, alcohol can increase anxiety in some people. Re c e n t l y, investigators attempted to determine whether alcohol produced a specific d e c rease in negative affect or whether it simply reduced emotional arousal acro s s the board, muting the intensity of any emotion (Stritzke et al. 1995). The study suggested that alcohol generally re d u c e s emotional a rousal, rather than specifically diminishing responses occurring during positive emotional states. If the effect of alcohol consumption is generally to lower emotional arousal, howe ve r, then it is unclear h ow alcohol acts to enhance emotional state. In ve s t i g a t o r s h a ve suggested that alcohol's effects on emotional reactivity may re s u l t f rom its effects on cognition and information p rocessing, rather than on motiva t i o n a l systems involving affect and emotion.

External Motivations To Drink
Social influences, norms, and contexts also play a role in the motivation to drink. External motives to drink include the social rew a rds of projecting a particular image, as well as the avo i d a n c e of social rejection by complying with p e rc e i ved social norms that include consuming alcohol in social settings.

The Role of Cognition: Beliefs About Alcohol
Re s e a rchers also have investigated alcoh o l -related cognition (i.e., the conscious and unconscious knowledge or beliefs about alcohol) and the role of these beliefs in shaping alcohol-related behavior. Ba s e d on direct experience with the pharmacologic effects of alcohol and vicarious learni n g f rom parents, peers, and the bro a d e r c u l t u re and media, people deve l o p expectancies about the effects of alcohol consumption on their behavior. These expectancies then influence their decisions to drink. Theorists have suggested that cognition may in some cases be a bridge between the primary re i n f o rc i n g effects of alcohol and individual decisions to use it in a particular situation.

Explicit Beliefs and Expectations
Most people can describe many of their beliefs and expectations about alcohol. These beliefs are conscious or explicit. Expectations about alcohol's effects begin d e veloping early in life, even before a person drinks any alcohol, and pre d i c t f u t u re alcohol use. For example, yo u n g adolescents who told re s e a rchers that they b e l i e ved alcohol makes it easier to s o c i a l i ze we re shown in later years to h a ve increased their drinking over time to higher rates than did their peers without this belief (Smith et al. 1995). Data also suggest that expectancies and the experience of drinking have re c i procal effects. Not only do expectancies p redict later drinking but drinking experiences shape later expectancies about alcohol's effects.

Implicit Beliefs and Expectations
Re s e a rchers also have attempted to identify the alcohol-related beliefs, memo ry associations, and emotional states that are activated more spontan e o u s l y, without conscious aware n e s s -t e r m e d "implicit cognition"-and to study their role in drinking behavior. Such studies h a ve measured associative memory p rocesses in diverse ways, including inve st i g a t i n g h ow people at various ages mentally organize associations betwe e n alcohol and its effects, measuring fre e associations to alcohol-related words and p i c t u res, and observ i n g h ow exposure to an alcohol-related concept affects a part i c i p a n t's response to later stimuli.
Little is yet known about the re l ationship between implicit and explicit beliefs about alcohol and the potential d i f f e rences in the way that the two types of knowledge influence alcohol use. On e hypothesis suggests that conscious, explicit expectations influence alcohol use thro u g h deliberate, conscious decisionmaking. In contrast, unconscious memory associations may influence alcohol use more spontaneously when the expectations are t r i g g e red in an immediate situation.

Conclusions
The ultimate goal of genetic analyses, such as QTL studies, in alcohol re s e a rc h is identifying the genes that contribute to the development of alcoholism. Analysis of these genes would allow a rapid exploration of the biochemical underpinnings of alcohol's actions and would link behavi o r a l change to underlying genetic predisposition and biochemical action. Although no equivalent to human alcoholism exists in animals, genes i d e n t i f i e d in animal models almost certainly have human equivalents that are also invo l ve d in alcohol's actions and that may pre d i s-pose to human alcoholism. Such genes and the proteins they encode are potent targets for intervention, both diagnostic and pharmacologic. It seems certain that the results of genetic analyses will be exploited dramatically in the next century to provide a variety of "designer dru g s , " perhaps targeted to individual pro b l e m s associated with particular forms of alcohol abuse. Because mapping the genes that influence genetically complex diseases p resents difficult challenges for inve s t i g ators pro g ress on these diseases has been much slower than pro g ress in gene mapping for single-gene disord e r s .
Twin studies, which explore the re l ationship between alcoholism and other traits, continue to contribute to the formulation of a more biologically va l i d definition of the disease and to the characterization of disease subtypes that may ultimately prove to have differing genetic bases. Ac h i e vement of these objective s would greatly expedite the gene searc h . Fu rther pro g ress tow a rd the precise identification of genes influencing pre d i s p o s i-tion to alcoholism will depend on the d e velopment of improved tools for the g e n e -d i s c ove ry enterprise. Fo re m o s t among these tools will be more sophisticated statistical methods, a complete human gene map, and a catalogue of the major human genetic variations. On c e genes influencing the predisposition to alcoholism have been identified, a major n ew challenge confronting genetic epidemiologists will be to understand how such genes interact with enviro n m e n t a l factors to influence the development of alcoholism in the general population.
Re s e a rch on psychosocial factors in alcohol consumption and alcoholism encompasses a broad range of inve s t igations, all aimed at understanding h ow multiple biological and psyc h o s ocial risk factors interact to influence a l c o h o l -related behavior. Re s e a rch on familial transmission of alcoholism in p a rticular focuses on how genetic vulnerabilities are translated in the context of the family and social enviro n m e n t into alcoholism.
Recent re s e a rch traces the evo l u t i o n of the disorder of alcoholism along the life span and teases out the emotional and c o g n i t i ve motivational factors that induce people to drink. By constructing models of how the risk factors identified interact and then testing these models empirically, scientists are identifying risk factors for alcohol misuse as well as potential media t o r s and moderators of this risk. The ultimate goal of this re s e a rch is to deve l o p p re ve n t i ve interventions that target these risk and pro t e c t i ve factors in order to reduce the pre valence of alcohol-re l a t e d illness and death. s